Arginine vasopressin (AVP) and related peptides, when administered exogenously, prolong the duration of tolerance to ethanol. The similarities between neurohypophyseal peptide effects on tolerance and previously reported effects on memory consolidation supported the hypothesis that these phenomena may share underlying mechanisms. Using peptide agonists that interact selectively with vasopressin V1 and V2 receptors, we have characterized as V1 the receptors in brain that mediate the ability of vasopressin to maintain ethanol tolerance. A role for endogenous AVP, acting at brain V1 receptors, in the maintenance of tolerance was supported by the finding that a V1-selective antagonist, given alone, enhanced the rate of loss of ethanol tolerance, while a V2-selective antagonist did not. In the periphery, V1 vasopressin receptors mediate peptide-induced alterations in calcium mobilization. The ability of AVP to maintain ethanol tolerance was previously shown to depend on the presence of intact noradrenergic systems in brain, and the interaction of AVP with neuronally localized V1 receptors may alter norepinephrine release, and thus modulate tolerance. Vasopressin, as well as oxytocin and related peptides, were found to block or delay the development of ethanol tolerance. The two actions of AVP may be mediated via different receptors. The role of endogenous hormone in the development and maintenance of ethanol tolerance is also being investigated through studies of the biosynthesis and release of AVP in hypothalamus, posterior pituitary and other tissues (anterior pituitary, testis, and Leydig cell cultures). These studies will investigate mRNA, neurophysin and hormone levels during chronic ethanol treatment leading to the development of tolerance. Preliminary studies indicate that both hypothalamic and extrahypothalamic hormone synthesis are increased by dehydration. Other physiological regulators are also being studied. Understanding the role and mechanism of action of AVP in development, expression and dissipation of tolerance to ethanol may lead to benign means for the manipulation of tolerance and, possibly, of ethanol intake.